Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy DOI Creative Commons
Markus Grosch, Laura Schraft,

Adrian Chan

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июнь 22, 2023

Dilated cardiomyopathy is the second most common cause for heart failure with no cure except a high-risk transplantation. Approximately 30% of patients harbor heritable mutations which are amenable to CRISPR-based gene therapy. However, challenges related delivery editing complex and off-target concerns hamper broad applicability CRISPR agents in heart. We employ combination viral vector AAVMYO superior targeting specificity muscle tissue base editors repair patient cardiac splice factor Rbm20, aggressive dilated cardiomyopathy. Using optimized conditions, we >70% cardiomyocytes two Rbm20 knock-in mouse models that have generated serve as an vivo platform our strategy. Treatment juvenile mice restores localization defect RBM20 75% cells splicing targets including TTN. Three months after injection, dilation ejection fraction reach wild-type levels. Single-nuclei RNA sequencing uncovers restoration transcriptional profile across all major cell types whole-genome reveals evidence aberrant editing. Our study highlights potential combined achieve treatment hereditary diseases.

Язык: Английский

Spatially resolved multiomics of human cardiac niches DOI Creative Commons
Kazumasa Kanemaru, James Cranley, Daniele Muraro

и другие.

Nature, Год журнала: 2023, Номер 619(7971), С. 801 - 810

Опубликована: Июль 12, 2023

The function of a cell is defined by its intrinsic characteristics and niche: the tissue microenvironment in which it dwells. Here we combine single-cell spatial transcriptomics data to discover cellular niches within eight regions human heart. We map cells microanatomical locations integrate knowledge-based unsupervised structural annotations. also profile cardiac conduction system

Язык: Английский

Процитировано

154
Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches DOI
Stéphane Heymans, Neal K. Lakdawala, Carsten Tschöpe

и другие.

The Lancet, Год журнала: 2023, Номер 402(10406), С. 998 - 1011

Опубликована: Сен. 1, 2023

Язык: Английский

Процитировано

84
Resident cardiac macrophages: Heterogeneity and function in health and disease DOI Creative Commons
Rysa Zaman, Slava Epelman

Immunity, Год журнала: 2022, Номер 55(9), С. 1549 - 1563

Опубликована: Сен. 1, 2022

Язык: Английский

Процитировано

72
Immunology of human fibrosis DOI
Mallar Bhattacharya, Prakash Ramachandran

Nature Immunology, Год журнала: 2023, Номер 24(9), С. 1423 - 1433

Опубликована: Июль 20, 2023

Язык: Английский

Процитировано

65
Integration of Single-Cell RNA-Seq Datasets: A Review of Computational Methods DOI Open Access
Daehee Hwang, Geun Hee Han, Eun‐Soo Jung

и другие.

Molecules and Cells, Год журнала: 2023, Номер 46(2), С. 106 - 119

Опубликована: Фев. 1, 2023

With the increased number of single-cell RNA sequencing (scRNA-seq) datasets in public repositories, integrative analysis multiple scRNA-seq has become commonplace.Batch effects among different are inevitable because differences cell isolation and handling protocols, library preparation technology, platforms.To remove these batch for effective integration datasets, a methodologies have been developed based on diverse concepts approaches.These methods proven useful examining whether cellular features, such as subpopulations marker genes, identified from certain dataset, consistently present, or their conditiondependent variations, increases particular disease-related conditions, observed generated under similar distinct conditions.In this review, we summarize approaches pros cons reported previous literature.

Язык: Английский

Процитировано

45
Targeting immune–fibroblast cell communication in heart failure DOI
Junedh M. Amrute, Xin Luo, Vinay Penna

и другие.

Nature, Год журнала: 2024, Номер 635(8038), С. 423 - 433

Опубликована: Окт. 23, 2024

Язык: Английский

Процитировано

27
LIANA+ provides an all-in-one framework for cell–cell communication inference DOI Creative Commons
Daniel Dimitrov, Philipp Schäfer, Elias Farr

и другие.

Nature Cell Biology, Год журнала: 2024, Номер 26(9), С. 1613 - 1622

Опубликована: Сен. 1, 2024

The growing availability of single-cell and spatially resolved transcriptomics has led to the development many approaches infer cell-cell communication, each capturing only a partial view complex landscape intercellular signalling. Here we present LIANA+, scalable framework built around rich knowledge base decode coordinated inter- intracellular signalling events from single- multi-condition datasets in both data. By extending unifying established methodologies, LIANA+ provides comprehensive set synergistic components study communication via diverse molecular mediators, including those measured multi-omics is accessible at https://github.com/saezlab/liana-py with extensive vignettes ( https://liana-py.readthedocs.io/ ) an all-in-one solution inference.

Язык: Английский

Процитировано

25
Spatial multi-omics: novel tools to study the complexity of cardiovascular diseases DOI Creative Commons
Paul Kießling, Christoph Kuppe

Genome Medicine, Год журнала: 2024, Номер 16(1)

Опубликована: Янв. 18, 2024

Abstract Spatial multi-omic studies have emerged as a promising approach to comprehensively analyze cells in tissues, enabling the joint analysis of multiple data modalities like transcriptome, epigenome, proteome, and metabolome parallel or even same tissue section. This review focuses on recent advancements spatial multi-omics technologies, including novel computational approaches. We discuss low-resolution high-resolution methods which can resolve up 10,000 individual molecules at subcellular level. By applying integrating these techniques, researchers recently gained valuable insights into molecular circuits mechanisms govern cell biology along cardiovascular disease spectrum. provide an overview current approaches, with focus integration datasets, highlighting strengths weaknesses various pipelines. These tools play crucial role analyzing interpreting facilitating discovery new findings, enhancing translational research. Despite nontrivial challenges, such need for standardization experimental setups, analysis, improved tools, application holds tremendous potential revolutionizing our understanding human processes identification biomarkers therapeutic targets. Exciting opportunities lie ahead field will likely contribute advancement personalized medicine diseases.

Язык: Английский

Процитировано

24
AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy DOI Creative Commons
Iris Wu,

Aliya Zeng,

Amara Greer-Short

и другие.

Communications Medicine, Год журнала: 2024, Номер 4(1)

Опубликована: Март 18, 2024

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with arrhythmias and an increased risk of sudden death. Currently, there are no approved treatments that address the underlying genetic cause this disease, representing significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding desmosomal protein, account for approximately 40% ARVC cases result reduced gene expression.

Язык: Английский

Процитировано

21
Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy DOI Creative Commons
Bryan Z. Wang, Margaretha Morsink, Seong Won Kim

и другие.

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(1)

Опубликована: Янв. 1, 2025

Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function other cardiac cell types understudied. In this study, we used an isogenic pair BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate role hiPSC-derived fibroblasts (CFs). Analysis type-specific conditional knockout engineered heart tissues revealed essential contribution CF contractility fibrosis, recapitulating phenotype DCM. BAG3-/- CFs, observed increased sensitivity TGF-β signaling activation a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, showed that loss transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 mediating its ubiquitination proteasomal degradation. To further validate these results, performed single-nucleus RNA sequencing tissue from DCM patients carrying pathogenic variants. variants fibrotic gene expression CFs. Together, results extend our understanding roles disease beyond cardiomyocyte-centric view highlight ability tissue-engineered hiPSC models elucidate aspects disease.

Язык: Английский

Процитировано

2